COVID-19BOLETIM RAMB

Número 21 11 de julho de 2020

Mert İlker HayıroğluTufan ÇınarAhmet İlker Tekkeşin

Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review

BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 2

Em um momento em que há uma emergência mundial de saúde pública, é fundamental que o conhecimento científico ge-rado durante a pandemia chegue rapidamente à classe médica classe médica.

Dentro desta dinâmica a Revista da Associação Médica Brasi-leira (Ramb) está adotando uma série de medidas a fim de acelerar o processo editorial para publicação de artigos sobre a Covid-19. A partir de hoje (14/04/2020), a AMB publicará o Boletim Ramb Covid-19, que antecipará os artigos científicos selecionados pelos editores da Ramb sobre o tema.

“Os artigos foram escritos por especialistas e selecionados den-tro dos critérios da Ramb para esclarecer temas fisiopatológicos, assim como oferecer orientações de prevenção e tratamento da doença. Dessa forma, esperamos colaborar com os médicos para o melhor atendimento aos seus pacientes, com a disponibilidade mais ágil desses artigos, antes de sua publicação na Ramb”, co-menta Carlos Serrano Jr., editor-chefe da Ramb.

Para o diretor científico da AMB, Antonio Carlos Palandri Cha-gas, “neste momento ímpar vivido no mundo por conta da pan-demia de Covid-19, a AMB cumpre seu papel de estar levando à comunidade científica brasileira os recentes artigos sobre os mecanismos fisiopatológicos e aspectos clínicos relevantes dessa situação que assola a saúde pública”.

Antonio Carlos Palandri Chagas

Carlos Serrano Jr.

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BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 5

Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review

Mert İlker Hayıroğlu1

Tufan Çınar2

Ahmet İlker Tekkeşin1

1. Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey

2. Department of Cardiology, Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey

INTRODUCTIONAn outbreak of a newly described virus, severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2), has appeared worldwide with a fre-quent occurrence of pneumonia and its local or/and systemic complica-tions. The virus has been named SARS-CoV-2 in China, following its first isolation from patients with pneumonia1. The disease has been later referred to as coronavirus dis-ease 2019 (Covid-19) by the World Health Organization (WHO) in Feb-ruary/20202. The severity of Covid-19 increases due to the development of acute respiratory distress syndrome (ARDS) and sepsis if not limited to pneumonia. Patients with Covid-19 have an incidence of ARDS of 15.9-29%, in addition to ARDS, sepsis is observed in all deceased patients3-5. Moreover, disseminated intravascu-lar coagulation (DIC) is one of the major underlying causes of death in these patients. Consumption coagu-lopathy, which should be obviated in order to decrease mortality, arises in DIC with a decrease in fibrinogen and an increase in D-dimer levels. In fact, fibrinogen and one of its end prod-ucts, D-dimer, have also been reported to have predictive value regarding the mortality of patients with non-Covid sepsis secondary to complications of DIC6,7. Therefore, anticoagulation, considering its mortality benefits in non-Covid sepsis, may also have an important role in the treatment of Covid-198.

In the current treatment strategy, patients with Covid-19 receive hydroxy-chloroquine and/or azithromycin as a first-line therapy9. Favipiravir, remde-sivir, and lopinavir/ritonavir are the second line available after the failure

SUMMARYINTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly described virus responsible for the outbreak of the coronavirus disease 2019 (Covid-19), named by the World Health Organization (WHO) in February/2020. Patients with Covid-19 have an incidence of acute respiratory distress syndrome (ARDS) of 15.9-29% and sepsis is observed in all deceased patients. Moreover, disseminated intravascular coagulation (DIC) is one of the major underlying causes of death among these patients. In patients with DIC, there is a decrease in fibrinogen and an increase in D-dimer levels. Some studies have shown that fibrinogen and one of its end products, D-dimer, might have a predictive value for mortality in patients with non-Covid sepsis secondary to complications of DIC. Therefore, anticoagulation, considering its mortality benefits in cases of non-Covid sepsis, may also have an important role in the treatment of Covid-19. METHODS: We reviewed the literature of all studies published by April 2020 on patients infected with Covid-19. Our review was limited to D-dimer and fibrinogen changes and anticoagulation recommendations. RESULTS: Anticoagulation therapy can be started following the DIC diagnosis in Covid-19 patients despite the bleeding risks. In addition, the current evidence suggests a routine use of anticoagulation, particularly in patients with higher D-dimer levels (> 3.0 μg/mL). CONCLUSION: Covid-19 is a systemic, hypercoagulable disease requiring more studies concerning treatment. Aanticoagulation is still an issue to be studied, but D-dimer rise and disease severity are the indicative factors to start treatment as soon as possible. KEYWORDS: Coronavirus Infections. Anticoagulants. Disseminated intravascular coagulation. Fibrin fibrinogen degradation products. Blood Coagulation.

RESUMOINTRODUÇÃO: O coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) é o vírus responsável pelo surto recentemente batizado de doença pelo coronavirus 2019 (Covid-19) pela Orga-nização Mundial de Saúde (OMS) em fevereiro/2020. Os doentes com Covid-19 têm uma incidência de síndrome de dificuldade respiratória aguda (SDRA) de 15,9-29% e sepse é observada em todos os pacientes que vêm a óbito. Além disso, a coagulação intravascular disseminada (DIC) é uma das principais causas subjacentes de morte entre esses pacientes. Em pacientes com DIC, ocorre com uma diminuição do fibrinogênio e um aumento dos níveis de dímero D. Alguns estudos mostraram que o fibrinogênio e um dos seus produtos finais, o dímero D, podem ter um valor preditivo para a mortalidade em pacientes com sepse não relacionada à Covid-19 decorrente de complicações da DIC. Portanto, a anticoagulação, considerando seus benefícios quanto à mortalidade na sepse não relacionada à Covid-19, pode também ter um papel importante no tratamento da Covid-19.MÉTODOS: Realizamos uma revisão de todos os estudos publicados até abril de 2020 sobre pacientes infectados com Covid-19. A nossa revisão limitou-se a alterações no dímero D, nos fibrinogênios e recomendações de anticoagulantes.RESULTADOS: A terapêutica anticoagulante pode ser iniciada após o diagnóstico de DIC em pacientes com Covid-19 apesar dos riscos de hemorragia. Além disso, a evidência atual sugere o uso rotineiro da anticoagulação, principalmente em pacientes com níveis mais elevados de dímero D (> 3, 0 µg/mL).CONCLUSÃO: A Covid-19 é uma doença sistêmica e hipercoagulável que requer mais estudos em relação ao tratamento. A anticoagulação ainda é uma questão a ser estudada, mas o aumento de dímeros D e a gravidade da doença são os fatores indicativos para o início do tratamento o mais rápido possível.PALAVRAS-CHAVE: Infecções por Coronavirus. Anticoagulantes. Coagulação intravascular disseminada. Produtos de Degradação da Fibrina e do Fibrinogênio. Coagulação Sanguínea.

BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 6

of first-line therapy, but they can also be used as a first-line agent10. Despite limited data concerning drug therapies against Covid-19, biologic agents (tocili-zumab, anakinra, etc.), Jak inhibitors, and corticosteroids are also available options if hemophagocytic lympho-histiocytosis occurs due to cytokine storm11. Furthermore, there is lim-ited data and no consensus in terms of the management of patients who can take advantage of anticoagulant treatment throughout their disease course. Thus, our review article aims not only to summarize and analyze existing literature reporting on fibrin-ogen and D-dimer in patients infected with Covid-19 but also to discuss the role of anticoagulation strategies in Covid-19 patients as a complement to standard therapies.

METHODSA review of the literature has been implemented on the subject of anti-coagulation treatment in patients infected with Covid-19. We have included the Pubmed, Embase, and Cochrane databases. They were searched on April 2020 using the following search inputs: ‘covid-19, coagulation’ (21 outputs), ‘covid-19, coagulant’ (5 outputs), ‘covid-19, thrombus (17 outputs)’ and the word ‘coronavirus’ was used instead of covid-19 in all inputs. If eligible man-uscripts featured coagulation abnor-malities and potential anticoagulation regimens in the treatment of Covid-19 patients, they were included in our review. Any further articles were obtained after the examination of the references from the relevant articles. Our review is limited to D-dimer and fibrinogen changes and anticoagu-lation recommendations, thus we did not include articles on the use of anti-platelets or anti-agregants in Covid-19 patients.

Fibrinogen and D-dimerFibrinogen, which is known as one of the acute phase proteins, is syn-thesized in high quantity by the liver

in response to IL-1 and IL-6 derived stimulation, as well as is involved in fibrin formation as the last step of a triggered coagulation activity12. The value of fibrinogen has already been demonstrated it has been chosen as one of the scoring parameters in DIC diagnosis according to The Interna-tional Society for Thrombosis and Haemostasis (ISTH)12. Hence, fibrin-ogen has intrinsically appeared as the subject of investigation in the Covid-19 pandemic era due to the close rela-tionship between Covid-19 and DIC. The dynamic changes in fibrinogen levels are remarkable and need to be addressed in Covid-19 patients. Table 1 summarizes all the investigations applied in Covid-19 patients concern-ing fibrinogen and D-dimer. Han et al.13 have investigated the changes in blood coagulation of patients infected with Covid-19 by comparing them with healthy controls. It is obvious that the level of fibrinogen and its degradation products are not only higher in Covid-19 patients compared to healthy controls (5.02 vs. 2.90 g/L, p< 0.001) but also higher in critical Covid-19 patients compared to mild or moderate cases (5.59 vs. 5.10 g/L, p< 0.01)13. On the other hand, fibrin-ogen is reported to be non-significant between surviving and non-surviving Covid-19 patients in a different cohort (5.16 vs. 4.51 g/L, p= 0.149)14. Thus, it is not difficult to interpret this as an admission that fibrinogen is expected to be higher than normal levels in hos-pitalized patients; however, it might not have a predictive value for mor-tality in Covid-19 patients. Fibrinogen should be evaluated together with D-dimer levels in order to have more proper prognostic assumptions since its gradual decrease together with higher D-dimer levels have a role in diagnosing DIC status as early as pos-sible in sepsis.

D-dimer is the soluble plasmin-me-diated degradation product of fibrin, which is produced after activation of coagulation and fibrinolysis 25 (Figure 1). D-dimer, which is also determined

as one of the diagnostic criteria of DIC, is usually used in order to diag-nose or exclude thrombotic events such as deep venous thrombosis or pulmonary embolism15. Venous thromboembolism (VTE) is a frequent complication of critical illnesses, par-ticularly in patients treated in inten-sive care units (ICU). The frequency of VTE has been reported to be 13% in patients of a respiratory inten-sive care unit26. On the other hand, the incidence of VTE has been 25% in patients with severe Covid-19 in the ICU, which also represents a hypercoagulable process in Covid-19 patients15. The D-dimer levels are also higher in patients with DVT compared to non-DVT. (5.2 vs. 0.8 μg/mL, p< 0.001) D-dimer within normal limits has been already known to have a higher sensitivity but lower specificity for acute thrombosis. Since we expe-rience higher D-dimer levels in most Covid-19 patients, it is also important to determine a specific level to predict thrombosis. Cui et al.15 have proposed 3.0 μg/mL as the cut off value to pre-dict VTE with a sensitivity of 76.9%, a specificity of 94.9%, and a nega-tive predictive value of 92.5%. The serum level of D-dimer has been also reported to be higher if the severity of the disease increases16-19. Despite expectancy of higher D-dimer levels in severe Covid-19 patients, it is import-ant to observe statistically significant D-dimer levels in moderate Covid-19 pediatric patients compared to milder ones (0.36 vs. 0.21μg/mL, p< 0.028)17. However, in a different cohort with fewer patients, there has been no difference in terms of D-dimer level in Covid-19 patients without or with aggravation (0.29 vs. 0.28 mg/dL, p= 0.922) 20. Nevertheless, if we consider D-dimer as a prognostic marker, it has been significantly higher in patients with ARDS and independently associ-ated with a higher risk of ARDS devel-opment (1.16 vs. 0.52 μg/mL, p< 0.001; OR= 1.03, 95%: 1.01 – 1.04; p< 0.001)21. Noteworthy, D-dimer has been proved to be higher in non-surviving patients

BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 7

TABLE 1. STUDIES PRESENT THE COAGULATION PARAMETERS IN PATIENTS WITH COVID-19 INFECTION

Studydesign

Studypopulation

Coagulation parameters

Results Pvalue

Supplementaryinformation

Zhou et al.2 Retro-spective

Covid-19 patients survivor (n= 137) vs. Covid-19 patients non-survivor (n=54)

D-dimer, μg/mL

0.6 vs. 5.2 < 0.001 *Value of D-dimer above 1was associated with 18-fold higher mor-tality [OR= 18.42, 95%CI: 2.64-128.55, p= 0.0033].

Han et al.13 Retro-spective

Control (n=40) vs. Covid-19 patients (n=94)

D-dimer, mg/dlFibrinogen, g/L

0.26 vs. 10.362.90 vs. 5.02

< 0.001< 0.001

*Significantly higher D-dimer and fibrin-ogen levels were present in patients with Covid-19 diseases.

Tang et al.14 Retro-spective

Covid-19 surviving pa-tients (n= 162) vs. Covid-19 non-surviving patients (n= 21)

D-dimer, mg/dlFibrinogen, g/L

0.61 vs. 2.124.51 vs. 5.16

<0.0010.149

*D-dimer level above 3 and fibrinogen level below 1 were present in 85.7% and 28.6%, respectively, in Covid-19 patients who developed DIC.

Cui et al.15 Retro-spective

Covid-19 non-VTE patients (n=61) vs. Covid-19 VTE patients (n= 20)

D-dimer, μg/mL

0.8 vs. 5.2 < 0.001 *> 1.5 μg/mL as the D-dimer cut-off value to predicting VTE

Liu et al.16 Retro-spective

Mild Covid-19 patients (n= 26) vs. severe Covid-19 patients (n=4)

D-dimer, mg/dl

0.26 vs. 1.54 <0.001 *Severe Covid-19 patient had higher D-dimer values compared to mild cases.

Qui et al.17 Retro-spective

Mild Covid-19 pediatric patients (n= 17) vs. moderate Covid-19 pediatric patients (n=19)

D-dimer, μg/mL

0.21 vs. 0.36 0.028 *Moderate Covid-19 pediatric patients had increased D-dimer levels compared to those with mild Covid-19 disease

Chen et al.18

Retro-spective

Moderate Covid-19 patients (n= 10) vs. severe Covid-19 patients (n= 11)

D-dimer, μg/mL

0.3 vs. 2.6 0.029 *Severe Covid-19 patients had increased D-dimer levels compared to those with moderate Covid-19 disease

Zhang et al.19

Retro-spective

Non-severe Covid-19 patients (n= 82) vs. severe Covid-19 patients (n=56)

D-dimer, mg/dl

0.2 vs. 0.4 <0.001 *More elevated D-dimer levels were found in severe Covid-19 patients com-pared to non-severe Covid-19 patients

Zhou et al.20

Retro-spective

Covid-19 patients without aggravation (n= 12) vs. Covid-19 patients with aggra-vation (n=5)

D-dimer, mg/dl

0.29 vs. 0.28 0.922 *D-dimer was not a factor associated with disease progression in patients infected with Covid-19

Wu et al.21 Retro-spective

Covid-19 patients without ARDS (n= 117 ) vs. Covid-19 patients with ARDS (n= 84)

D-dimer, μg/mL

0.52 vs. 1.16 0.001 *D-dimer was associated with a higher risk of the development of ARDS [OR= 1.03, 95%CI: 1.01-1.04; p< 0.001].

Wu et al.21 Retro-spective

Covid-19 patients with ARDS (alive) (n= 40) vs. Covid-19 patients with ARDS (died) (n=44)

D-dimer, μg/mL

0.49 vs. 3.95 0.001 *D-dimer was associated with a higher risk of death in Covid-19 patients with ARDS [OR= 1.02, 95%CI: 1.01-1.04; p= 0.002].

Yin et al.22 Retro-spective

Covid-19 patients with severe pneumonia (n= 449) vs. non-Covid-19 patients with severe pneumonia (n=104)

D-dimer, μg/mL

1.94 vs. 2.52 0.140 *When D-dimer exceeded 3.0 μg/mL (six-fold the upper limit of normal), significantly lower mortality in heparin users than nonusers was found in Covid-19 patients (32.8% vs. 52.4%, p=0.017).

Tang et al.23

Retro-spective

Covid-19 surviving pa-tients (n= 315) vs. Covid-19 non-surviving patients (n= 134)

D-dimer, mg/dl

1.47 vs. 4.70 <0.001 *D-dimer was positively correlated with 28-day mortality in multivariate analysis [OR= 1.058, 95%CI: 1.028-1.090; p< 0.001].*The 28-day mortality of heparin users was lower than that of nonusers in patients with D-dimer > 6 fold the upper limit of normal (32.8% vs. 52.4%, p=0.017).

Zhang et al.24

Retro-spective

Covid-19 surviving patients (n= 89) vs. Covid-19 non-sur-viving patients (n= 6)

D-dimer, mg/L The D-dimer level was present as ≤ 1 and >1, respectively

0.001 *For the >1 mg/L group, 81.2% of the patients were severe Covid-19 cases, and 71.9% of the patients reached the composite endpoints including intensive care unit admission or death.*Higher D-dimer level was strongly related to severe Covid-19 pneumonia and composite endpoints, including intensive care unit admission or death (p< 0.001).

Abbreviations: VTE - venous thromboembolism; ARDS - acute respiratory distress . syndrome; DIC - disseminated intravascular coagulation; OR - odds ratio; CI - confidence interval.

BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 8

when compared to survivors in all retrospective investigations2,14,21-24. Several of these investigations have emphasized D-dimer exceeding 3.0 μg/mL (six-fold the upper limit of nor-mal) as a cut-off value for diagnosing 85.7% of the patients with DIC and guiding the anticoagulation treat-ment in order to decrease mortality secondary to Covid-1914,22. As a result, D-dimer has shown a promising value to direct anticoagulation strategies in the treatment of Covid-19.

AnticoagulationCovid-19 causes clinical complica-tions of multiple organs; however, the main complication occurs in the pulmonary system due to the high expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in the bronchial cells27. The destruction in the lungs has been presented in a histopatho-logical study showing alveolar sep-tal vascular congestion, eosinophil and lymphocyte infiltration, alveolar

exudation, and thrombosis in pulmo-nary circulation28. The main underly-ing mechanism, which is accused of higher coagulation tendency during Covid-19, is the over-activation of the immune system causing complement release syndrome. Elevated cytokines such as IL-6 stand as the key modula-tor in cellular immune response and are the trigger factor for coagulation disorders29. Therefore, anticoagula-tion treatment should be investigated in Covid-19 since a hypercoagulable state has been demonstrated in both cellular and organ levels.

Early anticoagulation has been suggested in order to reduce throm-bosis and microthrombus burden by Li et al.30, a professor who worked in frontline care in Wuhan. However, his suggestions are based upon his individual experience in Covid-19 patients. In fact, there are contro-versial articles and some comments about anticoagulation treatment in Covid-19. First of all, complement

activation is said to cause a sys-temic thrombotic tendency, thus complementary inhibition therapy should be the first target therapy to prevent thrombotic microangi-opathy, according to Campbell and Kahwash31. Moreover, similarities of lung findings have been exhib-ited between high altitude pulmo-nary edema (HAPE) and Covid-19 in a recent article, which suggested HAPE as an analogous disease to Covid-19. For this reason, acetazol-amide, nifedipine, and phosphodies-terase inhibitors have been proposed to be prescribed in Covid-19 since elevated fibrinogen level has been considered as an epiphenomenon of edema rather than coagulation activation32. Conversely, a retro-spective study has already tested the efficacy of anticoagulant ther-apy in Covid-19 and resulted in a reduction in mortality when D-di-mer exceeded 3.0μg/mL (32.8% vs. 52.4%, p= 0.017)23. The results may

BOLETIM RAMB COVID-19 • NÚMERO 21 > > > 9

be due to the hypercoagulable state of the disease, or the anti-inflamma-tory effect of anticoagulation, or the combination of these two reasons33. An interesting study on tissue plas-minogen activator (tPA) use for Covid-19 induced ARDS has shown amelioration in the PaO2/FiO2 ratio, which may be considered a clue for the necessity of anticoagulation prior to ARDS onset34. Anticoagulation ther-apy has also been beneficial in non-Covid 19 induced DIC, thus it should be immediately started following the DIC diagnosis in Covid-19 patients despite the bleeding risks35. In addi-tion, the current evidence suggests the routine use of anticoagulation, particularly in patients with higher D-dimer levels (> 3.0 μg/mL). How-ever, in light of existing data, the early administration of anticoag-ulation should be addressed with further investigations in Covid-19

patients without DIC. As a result, thromboprophylaxis in Covid-19 has been already suggested by posi-tion papers in several countries36,37. However, routine anticoagulation for Covid-19 patients should be tested by more studies since current evidence directs clinicians to the routine use of anticoagulation merely in severe Covid-19 patients.

CONCLUSIONCovid-19 is a systemic, hypercoagu-lable disease requiring more studies regarding treatment. Routine throm-boprophylaxis should be performed in all patients because of the nature of the disease and immobilization during treatment and isolation are required. Anticoagulation is still an issue to be studied, but increased D-dimer and disease severity are the indicative factors to start the treatment as soon as possible.

Conflict of interest

All authors declare they do not have any conflicts of interest.

Author contributionConception: M.İ.H., T.Ç., Design: M.İ.H., T.Ç.; Supervision: A.İ.T. Fund-ings: A.İ.T ; Materials: M.İ.H., T.Ç.; Data Collection: M.İ.H., T.Ç. Analy-sis: M.İ.H.; Literature Review: T.Ç., A.İ.T. ; Writer: M.İ.H. Critical Review: A.İ.T.

Submitted Date: 11-May-2020 Accepted Date: 23-May-2020

corresponding author: Tufan Çınar Department of Cardiology, Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, TurkeyTel: +90 (216) 542-2010 Fax: +90 (216) 542-2020E-mail: drtufancinar@gmail.com

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